Despite improvements in imaging techniques, surgery, and oncologic treatments, clinical outcomes for pancreatic ductal adenocarcinoma (PDAC) has not improved in 40 years. To improve outcomes, it is imperative to develop new imaging capabilities that enable early detection of PDAC and to identify PDAC precursor lesions that are likely to progress to invasive cancer. Pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN) represent two important classes of PDAC precursor lesions; risk stratification among these lesions represents a unique opportunity for personalized medicine in patients at risk for developing PDAC. We identified translocator protein (TSPO), an 18 kDa outer mitochondrial membrane protein involved in cholesterol metabolism, as a potential biomarker of PDAC. We evaluated TSPO immunoreactivity (IHC) in tissue microarrays of human PanINs, IPMNs, and PDAC. TSPO IHC was elevated in high-grade human PanIN lesions and high-grade subtypes of IPMN compared to low-grade PanIN and benign IPMN subtypes. These results prompted our exploration of the mechanistic basis of elevated TSPO levels in PanINs and evaluation of TSPO-PET imaging in genetically engineered mouse (GEM) models of PanIN to PDAC progression using 18[F] VUIIS-1008, a novel TSPO-PET ligand developed in our laboratory. Only modest uptake of 18[F] VUIIS-1008 and TSPO IHC levels were observed in PanINs arising in Pft1a-Cre/+; LSL- KrasG12D/+ mice, which rarely progress to PDAC. In contrast, robust uptake of 18[F]VUIIS-1008 and correspondingly increased TSPO IHC was observed in high-grade PanINs and PDACs arising in Pft1a-Cre/+; LSL-KrasG12D/+, Tgfbr2flox/+. Taken together, we hypothesize that TGF-? signaling pathway perturbations cause increased TSPO expression, via direct or indirect mechanisms. To further understand the temporal regulation of TSPO expression, and explore other TGF-? family receptor proteins, we propose examining two GEM of PDAC, Ptf1a-Cre/+;LSL-KrasG12D/+;Smad4flox/flox, a model that develops advanced IPMN precursor lesions, and a more penetrant model Ptf1a-Cre/+;LSL-KrasG12D/+;Smad4flox/flox;Ink4a/Arfflox/+, that develops IPMNs that advance to PDAC. By studying these mutations and correlative pathology and imaging, we will be able to In the current proposal, we seek to [1] Determine the ability of TSPO-PET to distinguish high-grade from low-grade PDAC precursors; [2] Use GEM to understand the molecular events that drive TSPO expression in PDAC disease progression; and [3] Study human pancreatic tissue to identify correlations between mutational status, TSPO expression, and disease severity, elucidate which mutations drive increased TSPO signal. We anticipate that these studies will lay the foundation for a trial evaluating TSPO-PET in patients at high-risk for developing PDAC.